Treating sepsis with vitamin C, thiamine, and hydrocortisone: Exploring the quest for the magic elixir.

The administration of ascorbic acid (vitamin C) alone or in combination with thiamine (vitamin B1) and corticosteroids (VCTS) has recently been hypothesized to improve hemodynamics, end-organ function, and may even increase survival in critically ill patients. There are several clinical studies that have investigated the use of vitamin C alone or VCTS in patients with sepsis and septic shock or are ongoing. Some of these studies have demonstrated its safety and potential benefit in septic patients. However, many questions remain regarding the optimal dosing regimens and plasma concentrations, timing of administration, and adverse effects of vitamin C and thiamine. These questions exist because the bulk of research regarding the efficacy of vitamin C alone or in combination with thiamine and corticosteroids in sepsis is limited to a few randomized controlled trials, retrospective before-and-after studies, and case reports. Thus, although the underlying rationale and mechanistic pathways of vitamin C and thiamine in sepsis have been well described, the clinical impact of the VCTS regimen is complex and remains to be determined. This review aims to explore the current evidence and potential benefits and adverse effects of the VCTS regimen for the treatment of sepsis.

Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017

OBJECTIVE: To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients. PARTICIPANTS: A multispecialty task force of 16 international experts in Critical Care Medicine, endocrinology, and guideline methods, all of them members of the Society of Critical Care Medicine and/or the European Society of Intensive Care Medicine. DESIGN/METHODS: The recommendations were based on the summarized evidence from the 2008 document in addition to more recent findings from an updated systematic review of relevant studies from 2008 to 2017 and were formulated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The strength of each recommendation was classified as strong or conditional, and the quality of evidence was rated from high to very low based on factors including the individual study design, the risk of bias, the consistency of the results, and the directness and precision of the evidence. Recommendation approval required the agreement of at least 80% of the task force members. RESULTS: The task force was unable to reach agreement on a single test that can reliably diagnose CIRCI, although delta cortisol (change in baseline cortisol at 60 min of <9 µg/dl) after cosyntropin (250 µg) administration and a random plasma cortisol of <10 µg/dl may be used by clinicians. We suggest against using plasma free cortisol or salivary cortisol level over plasma total cortisol (conditional, very low quality of evidence). For treatment of specific conditions, we suggest using intravenous (IV) hydrocortisone <400 mg/day for ≥3 days at full dose in patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy (conditional, low quality of evidence). We suggest not using corticosteroids in adult patients with sepsis without shock (conditional recommendation, moderate quality of evidence). We suggest the use of IV methylprednisolone 1 mg/kg/day in patients with early moderate to severe acute respiratory distress syndrome (PaO2/FiO2 < 200 and within 14 days of onset) (conditional, moderate quality of evidence). Corticosteroids are not suggested for patients with major trauma (conditional, low quality of evidence). CONCLUSIONS: Evidence-based recommendations for the use of corticosteroids in critically ill patients with sepsis and septic shock, acute respiratory distress syndrome, and major trauma have been developed by a multispecialty task force.

A safety evaluation of drotrecogin alfa (activated) in hematopoietic stem cell transplant patients with severe sepsis: lessons in clinical research.

We conducted an open-label, multicenter, single-arm clinical trial to investigate the safety and efficacy of drotrecogin alfa (activated) (Drot AA) in hematopoietic stem cell transplant (HSCT) patients with severe sepsis. Drot AA was administered as a continuous i.v. infusion of 24 microg/kg/h for 96 h. The target enrollment was 250 patients in 15-20 transplant centers over a 2-year period (March 2003-March 2005). However, after only 10 months, in December 2003, the trial was stopped due to a low enrollment of seven patients at three of the 15 sites that were open for accrual. Six of the seven patients completed the drug infusion. Two patients experienced serious bleeding events. The first patient developed a nonfatal diffuse alveolar hemorrhage 2 days after study-drug completion. The second patient had severe coagulopathy and developed a fatal intracranial hemorrhage on the third day of drug infusion. Three of the seven patients were alive 100 days after the HSCT. The slow enrollment rate was attributed to changes in transplant preparatory regimens, enhancements in antimicrobial prophylactic protocols and the use of antimicrobial-coated catheters. The small number of patients in this report precludes a definitive assessment of the safety and efficacy of Drot AA in HSCT patients.

Drotrecogin alfa (activated): a novel therapeutic strategy for severe sepsis.

Recent studies have highlighted the close link between activation of the coagulation system and the inflammatory response in the pathophysiology of severe sepsis. The protein C anticoagulant pathway plays an integral part in modulating the coagulation and inflammatory responses to infection. In patients with sepsis, endogenous protein C levels are decreased, shifting the balance toward greater systemic inflammation, coagulation, and cell death. On the basis of a single large randomised phase 3 trial, drotrecogin alfa (activated), a recombinant form of human activated protein C, was recently approved for the treatment of adult patients with severe sepsis and a high risk of death. Since its approval, several questions have been raised regarding the appropriate use of this agent. Given the increased risk of serious bleeding and the high cost of treatment, drotrecogin alfa (activated) should be reserved at this time for the most acutely ill patients with severe sepsis who meet the criteria that were used in the phase 3 trial.

Septic shock and multiple organ failure after hematopoietic stem cell transplantation: treatment with recombinant human activated protein C.

Severe sepsis with multiple organ failure after hematopoietic stem cell transplantation (HSCT) results in extremely high morbidity and mortality. Recent studies have highlighted the importance of sepsis-induced activation of the coagulation system in the pathophysiology of severe sepsis. Activated protein C is an important modulator of coagulation and inflammatory derangements during severe sepsis. Low levels of protein C occur in severe sepsis and are predictive of poor outcome. Recombinant human activated protein C (drotrecogin alfa (activated)) was recently approved by the Food and Drug Administration (FDA) for severe sepsis. The phase III trial that resulted in the approval of this agent, however, enrolled a general sepsis population and excluded patients undergoing HSCT. We report a case of fulminant septic shock and multiple organ failure after HSCT that was treated with drotrecogin alfa (activated) in addition to standard therapy, and recovered. The high mortality rates of patients who develop severe sepsis after HSCT demand that new avenues of treatment be considered for this very high-risk patient population. This case illustrates the potential application of a novel therapeutic approach. Clinical trials are warranted to further investigate the safety and efficacy of drotrecogin alfa (activated) in patients with severe sepsis after HSCT.

Acute respiratory failure in critically ill patients with cancer. Diagnosis and management.

Respiratory failure remains a common cause of admission to the ICU for patients with cancer, regardless of the nature of malignancy. The diagnosis and management of ARF in patients with cancer poses special challenges to the intensivist. Depending on the type of cancer, the degree of immunosuppression, underlying comorbidities, the modality of cancer treatment, progression or spread of underlying cancer, and disease- or therapy-associated complications are the most common causes of ARF in these patients. Despite significant advances in antineoplastic therapies and supportive management in the ICU, the mortality rate of patients with cancer with ARF remains high. Severity-of-illness scoring systems and mortality probability models, although useful in discriminating between survivors and nonsurvivors in large groups of critically ill patients, should not be used alone to justify reluctance in admitting individual patients with cancer with potentially reversible respiratory failure to the ICU. Close collaboration between oncologists and intensivists will ensure the establishment of clear goals and direction of treatment for every patient with cancer who requires mechanical ventilation.

Acquisition strategies for critical care technology.

Technological advances in critical care will undoubtedly find their way into the ICU of the 21st century. The challenge for critical care practitioners is to meticulously assess these innovations and adopt the most appropriate and efficient technologies that will improve unit function and staff efficiencies, support educational programs, and most importantly, enhance patient outcome at a reasonable cost. Hospital-based intensivists have excellent opportunities to establish leadership roles in the technology evaluation process by cultivating relationships with administrators, and through active participation in the hospital-based Technology Committee and the ICU-based multidisciplinary committee. The authors' experience has left them with the lasting impression that the evaluation and introduction of new technology is time consuming and requires perseverance and patience. Ultimately, it is hoped that technological breakthroughs coupled with a standardized approach to delivery of ICU services in the coming decades will ensure better and more efficient care to critically ill patients.

Bioartificial organ support for hepatic, renal, and hematologic failure.

The current strategy to the treatment of SIRS and MODS uses a multidisciplinary approach that emphasizes supportive therapy. Herein, we have presented a futuristic approach that focuses on replacing the function of failed organs using bioartificial technology (Table 1). Bioartificial organ technology may allow the intensivist to provide physiologic organ replacement either as a bridge to transplantation or as a "time-buying" element until native organs that have become acutely dysfunctional or nonfunctional in a variety of clinical settings, can recover their function or regenerate their mass. As bioartificial organ technology matures, it is conceivable as an ultimate goal that non-immunogenic bioartificial organs would be miniaturized or redesigned and acutely placed within the intracorporeal space as replacement organs.

Hearing loss in critical care: an unappreciated phenomenon.

OBJECTIVES: The objectives of this article are to review the physiology of hearing; identify acute pathologic and perceived causes of hearing loss in the adult critically ill patient; and to discuss its evaluation, treatment, and prevention. DATA SOURCES: Computerized bibliographic search of MEDLINE from 1966 to the present of all relevant articles in all languages on acute hearing loss in the adult population. DATA EXTRACTION: Data gathered from studies and reports of acute hearing loss as relates or potentially relates to the peri-intensive care unit (ICU) period. DATA SYNTHESIS: Hearing loss is an infrequent but potentially serious complication associated with critical illness. The causes of hearing loss in the ICU patient include mechanical or accidental trauma, administration of ototoxic medications, local or systemic infections, vascular and hematologic disorders, autoimmune diseases, and environmental noise. Patients who are elderly, have coexisting liver or renal failure, or who are receiving concomitantly administered ototoxic drugs are particularly at risk for developing hearing loss. A thorough assessment of potential causes of hearing loss and audiological examination should be undertaken on all ICU patients suspected of hearing loss. Mechanical, pharmacologic, and environmental strategies are available to decrease the incidence of hearing loss in this patient population. CONCLUSIONS: Hearing loss should be recognized as a potential clinical problem by intensivists. Its causes should be identified and appropriate evaluation and therapy initiated. High risk populations should be identified for preventive measures.

Isoproterenol regulates tumour necrosis factor, interleukin-10, interleukin-6 and nitric oxide production and protects against the development of vascular hyporeactivity in endotoxaemia.

Pro-inflammatory cytokines, such as tumour necrosis factor (TNF) and free radicals, such as nitric oxide (NO), are mediators of endotoxaemia. Catecholamines are in clinical use to treat the haemodynamic consequences of severe septic shock. Beta-adrenergic agonists exert many of their effects by elevation of intracellular cyclic AMP (cAMP) concentration. Cyclic AMP can modulate endotoxin-induced cytokine and NO production. Here we investigate the effect of isoproterenol pretreatment on the cytokine and NO production induced by bacterial lipopolysaccharide (LPS, 4-10 mg/kg). Pretreatment with isoproterenol (10 mg/kg) blunted the LPS-induced TNF response, increased the LPS-induced formation of interleukin-10 and interleukin-6 and reduced the LPS-induced production of NO in conscious mice. In anaesthetized rats, pretreatment with isoproterenol prevented the LPS-induced suppression of vascular contractility to norepinephrine in the thoracic aorta ex vivo. The hyporeactivity is due to expression of the inducible isoform of NO synthase (iNOS) and was restored by in vitro administration of NG-methyl-L-arginine (L-NMA), an inhibitor of NO synthase. However, L-NMA did not alter vascular contractility in control vessels or in rings taken from the LPS-treated rats pretreated with isoproterenol. Our findings suggest that, in addition to its haemodynamic actions, isoproterenol may also exert beneficial effects by modulating the endotoxin-induced inflammatory response.

Review: pneumothorax in patients with AIDS-related Pneumocystis carinii pneumonia.

A retrospective review was performed to describe the clinical characteristics, course, and outcome of pneumothorax for all patients admitted to Bellevue Hospital, New York, with AIDS who had Pneumocystis carinii pneumonia (PCP) diagnosed between January 1985, through July 1991. Of 1360 patients with AIDS and PCP, 67 patients (4.9%) were identified with pneumothorax; a group of 50 is the subject of this review. Of these 50 patients, 22 patients (44%) developed spontaneous pneumothorax, 15 patients (30%) developed pneumothorax during mechanical ventilation, and 13 patients (26%) had pneumothorax after an invasive procedure. Of the 22 patients with spontaneous pneumothorax, 8 had cystic parenchymal abnormalities on the chest radiograph and 6 had a history of PCP. The majority of patients were treated with tube thoracostomy and/or surgical intervention. All 15 patients who developed pneumothorax during mechanical ventilation died. Results of pathologic studies revealed varying degrees of interstitial inflammation and fibrosis interspersed with areas of hemorrhage and necrosis, and presence of P carinii cysts. Autopsy specimens obtained in two cases demonstrated multiple parenchymal cavities and evidence of an alveolar eosinophilic exudate with P carinii organisms. Spontaneous pneumothorax in patients with AIDS usually occurs in association with PCP and is associated with significant morbidity. Patients at risk include those with cystic lesions on chest radiograph and those patients with a history of PCP. Patients with AIDS and PCP who develop pneumothorax during mechanical ventilation have a poor outcome.

Adenosine receptor agonists differentially regulate IL-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice.

Adenosine released into the extracellular space by immunologic and nonimmunologic stimuli has been shown to regulate various immune functions. In this study we report that i.p. pretreatment of mice with CGS-21680 HCl (CGS), a selective agonist of A2 adenosine receptors, at 0.2 to 2 mg/kg caused an augmentation of plasma IL-10 levels induced by i.p. injection of LPS, but decreased plasma levels of LPS-induced TNF-alpha. 2-Chloro-N6-cyclopentyladenosine (CCPA), an agonist of A1 adenosine receptors, at 0.5 mg/kg diminished LPS-induced plasma TNF-alpha concentrations, but enhanced LPS-induced IL-10 levels only at the highest dose used (2 mg/kg). The specific A3 adenosine receptor agonist 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-beta- D-ribofuranuronamide, at 0.2 and 0.5 mg/kg potentiated LPS-stimulated IL-10 production and inhibited LPS-induced TNF-alpha production. LPS-induced plasma nitrite and nitrate levels (the breakdown products of nitric oxide (NO)) were suppressed by CGS and CCPA. In the RAW 264.7 macrophage cell line, pretreatment of the cells with both CGS and CCPA inhibited LPS-induced IL-10, TNF-alpha, and NO production, each in a concentration-dependent manner. The inhibitory effect of these drugs on cytokine and NO production was associated with improved mitochondrial respiration. Neither CGS nor CCPA affected the LPS-induced nuclear translocation of transcription factor nuclear factor-kappaB in these cells. These results demonstrate that adenosine receptor stimulation differentially modulates the LPS-induced production of IL-10, TNF-alpha, and NO in vitro and in vivo. The increase in LPS-induced IL-10 production and suppression of LPS-induced TNF-alpha and NO production caused by adenosine receptor activation may explain some of the immunomodulatory actions of adenosine released in excess during inflammatory and/or ischemic insult.

Splanchnic ischemia and gut mucosal injury in sepsis and the multiple organ dysfunction syndrome.

The incidence of multiple organ failure syndrome (MOFS) has increased dramatically in most intensive care units (ICU) in the United States and is now the leading cause of death after sepsis, trauma, and burns (1). Despite advances in resuscitation, availability of potent antibiotics, and modern techniques of organ support (2), the survival of critically ill patients with MOFS has not significantly improved since the syndrome was first described over 2 decades ago (3). In the ICU, the monitoring and management of critically ill patients with MOFS has relied, in large part, on readily available measurements of global hemodynamics and oxygen transport. Given the increased understanding of the special role of splanchnic hypoperfusion in the pathophysiology of sepsis and MOFS (4-5), investigators have focused more recently on regional blood flow and oxygen metabolism in these patients (6). In this article, we first present a clinical overview of sepsis and MOFS. Current concepts of the pathogenesis and pathophysiology of MOFS are discussed, with particular emphasis on the roles of splanchnic ischemia and gut barrier failure in the development of both sepsis and the maintenance of the systemic inflammatory response that leads to MOFS. Alterations in both global and regional oxygen transport in septic shock are described to emphasize the limitations of global monitoring in the assessment of splanchnic tissue oxygenation. The role of gastric tonometry in the monitoring of splanchnic oxygenation and its utility in critically ill patients is then analyzed. In addition, the effects and clinical implications of commonly used vasoactive agents on intestinal oxygenation are discussed. Finally, novel therapeutic strategies based on the "gut-origin hypothesis" of MOFS are reviewed.

Cytokine production and its manipulation by vasoactive drugs.

The management of severe sepsis includes the use of agonists of alpha- and beta-adrenergic, as well as of dopaminergic, receptors. Data suggest that the severe inflammatory immune response seen in sepsis can be modulated by stimulation and inhibition of these receptors both in vitro and in vivo. Specifically, release of tumor necrosis factor and interleukins can clearly be modified. Thus, pharmacologic agents directed at circulatory support may have significant potential for immunomodulation. Since the vasopressor and inotrope support of sepsis is not well standardized, variability in the resulting inflammatory mediator response may have consequences to the efficacy of new immunotherapies. This article provides an overview of the effect of the sympathetic nervous system activity and of receptor manipulation on cytokine response to endotoxin, and adds to the perspective on inhibition of phosphodiesterase in the therapy of septic shock.

Parenteral use of medium-chain triglycerides: a reappraisal.

Over the last two decades, the clinical use of intravenous fat emulsions for the nutritional support of hospitalized patients has become routine. During this time long-chain triglycerides (LCT) derived from soybean and/or safflower oils were the exclusive lipid source for these emulsions, providing both a safe calorically dense alternative to dextrose and essential fatty acids needed for biologic membranes and the maintenance of immune function. During the past decade, the availability of novel experimental triglycerides for parenteral use has generated interest in the use of these substrates for nutritional and metabolic support. Medium-chain triglycerides (MCT), long advocated as a superior substrate for parenteral use, possess many unique physiochemical and metabolic properties that make them theoretically advantageous over their LCT counterparts. Although not yet approved in the United States, preparations containing MCT have been widely available in Europe. Intravenous MCT preparations, either as physical mixtures or structured lipids, have been used clinically in patients with immunosuppresion, critical illness, liver and pulmonary disease and in premature infants. Despite great promise, the clinical data comparing the efficacy of MCT-based lipid emulsions to their LCT counterparts has been equivocal. This may be due in part to the limited nature of the published clinical trials. Measures of efficacy for parenteral or enteral nutritional products has taken on new meaning, in light of the reported experience using immunomodulatory nutrients. Current concerns about cost of medical care and resource use warrant careful deliberation about the utility of any new and expensive therapy. Until clinical data can fulfill expectations derived from animal studies, it is difficult to advocate the general use of MCT-based lipid emulsions. Future clinical studies with MCT-based emulsions should have clear outcome objectives sufficient to prove their theorized metabolic superiority.

Endovascular stented graft repair of a pseudoaneurysm of the subclavian artery caused by percutaneous internal jugular vein cannulation: case report.

In high-risk patients endovascular repair of a pseudoaneurysm with a stented graft is a safe and reasonable treatment option that can preclude significant morbidity and shorten hospital stay. We report a case of pseudoaneurysm of the subclavian artery after internal jugular vein cannulation that was treated successfully with an endovascularly inserted, stented graft. The case report highlights the importance of recognizing this unusual but serious complication of percutaneous internal jugular vein catheterization through careful clinical examination, prompt duplex scanning, and arteriography.